About the target of antitumor drugs

Trying to uncover my Achilles heel. The scientific community has been trying to figure out the cause of many cancers for years. It is not an easy task; however, having this information may be a means of fighting the tumor. And this disease is sometimes associated with a “postal code”; The way there involves a deadly pilgrimage, a journey that triggers other organs, spreading the malignancy and therefore endangering the patient’s life. It must not be forgotten that 90% of deaths caused by this pathology have a common denominator: metastases. Therefore, it is of utmost importance to stop this disease before it unleashes all its weapons.

To cut off tumors, Group for the Design and Synthesis of Bioactive Molecules of the University of Salamanca (USAL) is working on a project aimed at finding new molecules capable of inhibiting (blocking) mitotic proteins called kinesins. “These proteins are essential for cell division, a process called mitosis. Tumor tissues are characterized by excessive, uncontrolled cell division, which leads to abnormally rapid formation of new cells. If we can block mitotic kinesins, we can also block tumor development,” explains the professor. Maria Concepcion Perez Melero.

In this sense, he points out that they create these molecules after carefully studying the structure of the target proteins, the mitotic kinesins. “We select the atoms that will form these molecules and how they will be combined. After the design, we have to produce the molecules in the lab. We do this process through chemical reactions. It is important to emphasize that in our group, we strive to apply the principles of sustainable chemistry to carry out these chemical reactions; this means using environmentally friendly products and processes.

And once the new molecules are obtained, as described in detail, they will have to evaluate their biological activity on tumor cells. For this they have collaboration with Dr. Mercedes Garayoa from the Center for Oncological Research, a specialist in the biological evaluation of anticancer drugs, and who is also part of the project team, which, in addition, received one of the six scholarships awarded The Janet Mateu Foundation is nationwide in the 2024 call.

Perez Melero says protein inhibition is a mechanism used by many drugs, including some used to treat cancer. In fact, he adds, all anti-tumor drugs from the antimitotic group approved for clinical use target the protein tubulin. However, the researcher from the University of Salamanca points out that tubulin has many other functions in the cell that have nothing to do with mitosis. “Blocking these functions also causes side effects, mainly neurotoxicity,” he adds.

In the case of this work, he explains, they have chosen as targets proteins that do not seem to have other functions in the cell, so blocking them would not cause such side effects. Moreover, the head of this group claims that there are no drugs in clinical practice that would target these proteins. It is true, he admits, that some have been described that have reached different phases of clinical trials, but have not passed them. To this, according to him, it is worth adding that the Salamanca group’s goal is to block several of these proteins, which would ensure a synergistic effect and, ultimately, a more effective action. “The potential drugs created will be a new way of treating tumors that will complement those that currently exist,” says María Concepción Pérez Melero.

For this project, they note, they are using a variety of methods that will allow them to achieve their stated goals. For example, to design the compounds, they are using molecular modeling methods, or in other words, computational methods that help them in the detailed study of proteins and the best structures of potential inhibitors, as well as in the virtual analysis of the combination between the two.

When getting connectionsthey use tGeneral methods in the laboratory of organic synthesisemphasizing the use of methods compatible with sustainable chemistry, respecting the environment. The final step is the assessment of biological activity, which uses methods related to the cultivation of tumor cell lines, determination of cell proliferation, study of the cell cycle, etc.

An idea related towas born because they had been working for a long time to obtain new molecules that could act as drugs in different areas of research.one of which is dedicated to compounds that stop cell division (antimitotic action). “Given the inconvenience caused by the use of antimitotic drugs currently used in the clinic, we decided to consider alternative targets to the one they use. In addition, based on what is known about the structure and function of these alternative targets, as well as the compounds that interact with them, we decided to propose this project, supported by the Jean Mateu Foundation.

Its goal, he explains, is to evaluate the compounds’ ability to stop tumor cell proliferation. In addition, in the medium term, if the results of this first evaluation are positive, it says it will move on to in vivo evaluation in animals. which, in turn, implies compliance with additional aspects of drug effectiveness, such as access to the site of its action or possible toxicity, among other aspects. The end result of new drug research will be their evaluation in humans. (clinical trials) provided that previous results are positive.

In any case, the professor from the University of Salamanca insists that the road to this is very long and full of obstacles, since new drugs in all cases, and not only in this work, require exhaustive evaluation before being used. able to reach the stage of clinical trials in humans. In this regard, he emphasizes that an additional advantage of this study is its flexibility, since with each of these successive biological assessments, his proposal can be reformulated using additional molecules that can avoid the problems identified.

In his opinion,They are making steps in the right direction, but we are still lagging behind other more advanced communities in terms of research and knowledge transfer.. For this reason, he considers it “essential” that public administrations are aware that research is the key to achieving progress. In this sense, he adds that they need to step up their efforts to promote an ecosystem of fundamental and applied research in the Community that can compete with the best, including research centres and business networks.

When asked about the situation of young people, María Concepción Pérez Melero was clear that the economic crisis may have affected their motivation, as they see an uncertain future. “Research is a long-distance race, it takes a long time to reach a stable situation. In times of crisis, investment in research suffers significantly, and this contributes to limiting the opportunities for young people starting their research careers, meaning that they do not see their future clearly and may consider other options,” he reflects.

In his opinion, society is increasingly aware of the importance of scientific advances. Here he cites the example of the COVID-19 vaccine developed in record time or the recently launched drugs against hepatitis C or diabetes, which meant that scientific research was recognized by society. However, he regrets that this usually happens with very striking cases. For this reason, he explains that more work needs to be done so that we, as a society, realize that research is necessary to achieve advances that improve our quality of life. “It is very important to promote a greater scientific culture in society, and it is also important that scientists adequately communicate our work to the general public,” concludes the head of the Design and Synthesis of Bioactive Molecules research group at the University of Salamanca.